A drug is “a chemical substance used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well-being.
Medicament is a medicine or a substance used in a therapy. In this patent application, the terms “drug” and “medicament” have been used interchangeably.
A combination drug therapy has been gaining a lot of importance in recent times. The combination therapy in medicine involves administration of two or more therapeutically active ingredients. The active ingredient may be administered in a single dosage form or each active ingredient may be administered separately. The reasons of a combination therapy could be multiple—synergistic effects of drugs, reduction of side effect of the primary drug by an adjunct drug, avoidance of taking multiple tablets/capsules per day thereby savings on co-payment for different medicines and assurance of patient compliance to drug therapies.
In some embodiments of the combination drug therapy, the active ingredients are administered in a single dosage form. In those instances, it is important to show that different drugs combined in the same dosage form are stable during storage of the dosage form and should not interact physically or chemically with other drugs or excipients to produce degradation products. Also, each drug should show the desired release rate from the dosage form to get absorbed in sufficient quantities upon oral administration or release the drug to surrounding environment in case of other delivery routes.
Pharmaceutical capsule dosage forms are widely used in delivering drugs. Composition is the combination of parts or elements and it is the way in which something is put together. The composition of the capsule shell consists of a list of ingredients incorporated and their respective quantities.
There are two main two types of capsules—hard shell capsules and soft shell capsules.
Hard shell capsules, also called hard capsules herein, have two parts, the body and the cap. The body and the cap telescopically engage one another to define an interior volume of the hard capsule that typically holds dry ingredients, often in powder or granulated form. The body and the cap of a hard capsule have sufficient rigidity that the body and cap may form “snap connections” that resist separation of the body and cap after telescopic engagement.
Some types of hard shell capsules are formed from compositions that include polymers that have gelled or otherwise hardened and thereby form a polymeric system forming a hard polymer structure defining the shape of the body and cap. Polymers used to form polymeric systems that can form hard polymer structures include, but are not limited to, gelatins and carrageenans.
Soft shell capsules, also called softgels herein, are one piece, hermetically sealed shells often made of a gelatin, a plasticizer, and water. The plasticizer softens the gelatin and makes it flexible and non-rigid. A soft shell capsule typically holds an oil based liquid, suspension, or semisolid that does not dissolve the capsule's gelatin.
The term “hard” for a substance or matter is defined as a solid, firm substance or matter which is resistant to pressure and with an endurance.
Polymer is defined as a large molecule, or macromolecule, composed of many repeated subunits.
A system is defined as a set of connected things or parts forming a complex whole.
A polymeric system means a system in which one of the major components (in terms of quantity and functionality) is a polymer.
A structure is the arrangement of and relations between the parts or elements of something complex. A structure has a form, shape, composition, formation or a constitution. A hard polymer structure is defined as a rigid structure with polymer as a major component.
Hard capsule polymeric structure indicates a structure with a shape of capsule which is solid and does not change with time, external pressure and it has a polymer or a mixture of polymers as the major component. A hard capsule has a body and cap. The cap is placed on the body and pressed to stay locked. In contrast, the soft polymer capsule structure is soft in nature and can change the shape by some pressure. Soft capsule shells have higher amounts of water/moisture compared to the hard capsule shell.
The manufacturing process for the hard and soft capsule shells are completely different. As mentioned earlier, in the case of hard capsules, body and caps are prepared separately and are put together to form the entire capsule. Most of the soft capsules are prepared with gelatin. A solution of gelatin in water is prepared in a heated mixing tank. This also contains several excipients. In another tank, the filling material containing medicines is prepared. The filling material can be a solution (liquid or semi-solid) or a suspension. During the encapsulation stage, the fill material and gelatin shell ribbon come together to form the softgel capsule. The capsules are dried to remove excess moisture, but retain desired amount of moisture. In contrast, hard shell capsule shells contain significantly lower percent moisture.
The term “essential” means absolutely necessary. The hard shell capsule must have some essential physical and chemical properties. Property of a substance is a characteristics which helps to identify, describe, define or quantify the substance. The capsule shell is thin. Empty capsules shells are packed in big plastic bags and should not break during transportation and storage. After filling drugs, the capsules are stored in small bottles or in the blister packs. Capsule shells should not break during transportation and storage in these primary packaging systems. For that, they should have sufficient elastic stiffness, tensile strength and should not be brittle. The drug incorporated in the shell matrix should not affect the essential physical and chemical properties. The shell matrix is expected to dissolve once reaching the stomach or if the capsule is enteric coated, should dissolve in the intestine. Some chemicals such as aldehydes are known to crosslink gelatin. It slows down the dissolution of capsule shell. The drug should not affect the desired dissolution rate of the capsule shell. If the drug is hygroscopic, it may let capsule shell absorb more moisture than desired. Higher moisture level in the hard capsule can make them soft. In the worst-case scenario, capsules can become sticky and adhere to each other in the bottle.
The present disclosure relates to the hard capsule shell composition. The capsules are normally prepared using gelatin and other excipients. In recent times, several polymers have been employed to manufacture hard shell capsules. In 1977, Christen and Cheng patented (U.S. Pat. No. 4,026,986) hard shell capsules manufactured using 2-hydroxyalkyl starch. It facilitated the production of shells and produced improved shells. WO 1997004755 (International application PCT/EP1996/003263) prepared hard gelatin capsules with internal or external polymer coating using the double dipping technique. The inventors used polyvinyl alcohol and polyvinyl acetate polymers along with necessary additives.
Gennadios invented non-gelatin capsules (U.S. Pat. No. 6,214,376) comprising k-carrageenan, water soluble plasticizer, and dextrins. The composition also included hydrolyzed starch as a variation. U.S. Pat. No. 6,517,865 claimed hard and soft capsules comprising of water soluble cellulose ethers, hydrocolloids and sequestering agents. The capsules also comprised of a coating with polymers including cellulose acetate phthalate, hydromellose phthalate etc.
In 2004 patent by Chen et al. (U.S. Pat. No. 6,752,953), authors described the usage of other polymers such as cellulose derivatives including cellulose, cellulose ester, methylcellulose, hydroxypropyl methylcellulose etc., acrylates including polyacrylate, polymethylacrylate, poly(methacrylate-methylmethacrylate) etc., and polyolefins including polyethylene, polypropylene, polyvinyl chloride, polyvinyl alcohol etc. to prepare capsules. The inventors described a heat-melting method to prepare the capsule shells.
U.S. Pat. No. 8,029,821 used low-substituted cellulose ether to produce hard capsules. The inventors also proposed a method for capsule preparation. The pins were dipped in the alkaline solution of low-substituted cellulose ether followed by dipping in an aqueous acid solution to form a gel (low-substituted cellulose ethers are soluble in alkaline medium and form a gel in the acidic environment). The pins covered with the gel were further washed with water before the drying step.
U.S. Pat. No. 6,949,256 used a mixture of kappa carrageenan and iota carrageenan. Kappa carrageenan is known to form a strong gel in the presence of potassium cations. However, these tend to be brittle and exhibit syneresis (exudating of liquid portion of the gel). Iota carrageenan reacted with calcium cations and formed a weaker and more flexible gel. In the U.S. Pat. No. 8,105,625, Rajewski and Haslam prepared hard shell capsules with pullulan, a plasticizer and a dissolution enhancing agent. The capsules were meant to dissolve in the mouth cavity (orally dissolving capsules).
US patent application #2008/0274187 prepared hard capsule compositions comprising carrageenan, locust bean gum, xanthan gum, sorbitol, and pullulan. These capsules eliminated the problem of cracking, embrittlement, chipping and deformation due to water loss and mechanical stress.
US patent application #2010/0168410 described a composition of hard capsules of hydroxypropyl methylcellulose and the process of dip-coating manufacture. The dipping pins were heated at 55-95° C. and the polymer solution was maintained at 1 to 10° C. below its gelling temperature.
McConville et al. (Eur. J. Pharmaceutics & Biopharm. 57: 541-549 (2004)) prepared a capsule filled with low-substituted hydroxypropyl cellulose in which a propanol tablet was placed followed by an erodible tablet containing HPMC and lactose manufactured by either direct and wet granulation technique. In this case, the body of the capsule was pre-coated with insoluble ethyl cellulose suggesting the drug release only after the dissolution of the cap of the capsule. In this case, the capsule shell was not loaded with the drug—propranolol.
In the US patent application #2004/0146559, a film was formed on the inner surface of the capsule shell. The shell may have different properties to alter the drug release rates. In this patent, the core and the shell were manufactured in situ. In the present disclosure, the empty hard capsule shell composition containing the drug may be produced by the manufacturers of empty capsules (such as, Capsugel, Universal capsules, and Shionogi capsules).
In the U.S. Pat. No. 6,709,427, microspheres were encapsulated to produce microcapsules. The core technology was to prepare microspheres. Microcapsule is a totally different kind of drug delivery technique compared to the hard capsule shell dosage form. In the hard capsule shell dosage form, the drug granules or powder or microspheres are filled in the capsule shell body on which the cap is fitted.
In the US patent application #2003/0104062, the capsules core was loaded with the drug. The “capsule core” is the empty space within the capsule shells and not the capsule shell composition. Hollow is defined as an empty space. A “hollow core hard shell capsule” means a hard shell capsule with an empty space in the core. The shell surrounding the drug-containing core governs the release rate (zero order) of the drug by diffusion mechanism due to its swelling. The shell also promoted gastric retention of the capsules by swelling upon the imbibition of gastric fluid to a size that was retained in the stomach during the fed mode.
In the US patent application #2003/0104062, no drug was incorporated in the capsule shell composition. In another embodiment, the drug was incorporated in the shell so as to produce a burst effect. In this case, the same drug is incorporated in the core and in the shell/casing. In this patent, the preparation of capsule shell was part of the manufacturing process in situ. The desired zero order release, the manufacturing process and drug combination are the key differences between US patent application #2003/0104062 and the current patent application.
U.S. Pat. No. 7,666,398 by Uhrich K described the composition and method of preparation of a polymeric drug delivery system using polyanhydrides. Polyanhydrides linked low molecular weight drugs containing a carboxylic acid group and an amine, thiol, alcohol or phenol group within their structure. The inventors did not disclose the capsule as the drug delivery system.
Yamamoto et al. in their U.S. Pat. No. 5,756,123 described a capsule shell comprising of hydropropyl methylcelluose (HPMC), carrageenan as a gelling agent and calcium or potassium ions as the co-gelling agent. Carrageenan helped to improve the shapability of HPMC. Co-gelling agents assisted the gelation of carrageenan. Calcium ions were used for iota-carrageenan whereas potassium ions were used for kappa carrageenan. Carrageenan was not included in this composition as a therapeutically active agent. But it was used as part of the polymer structure of the capsule as a gelling agent to improve capsule properties.
Sakanishi et al in their US patent application #2006/0275361 described rapidly dissolving gelatin compositions. Although gelatin is water-soluble, it takes several minutes to dissolve in mouth to release their core material. The inventors added dissolution enhancing materials to the gelatin composition such as polyol plasticizer and water-insoluble particulate components. Polyols were selected from the group consisting of glycerin, propylene glycol, sorbitol, maltitol, xylitol, mannitol, erythritol, isomalt, lactitol and combinations thereof. One has to be very careful about understanding the definitions of “capsule shell-forming composition” and “core composition” Gelatin, polyol and water-insoluble component formed a “capsule shell-forming composition” with which, the capsules were formed. The “core composition” was the one which was filled in the above-mentioned capsules. The “core composition” may include sweeteners, flavors, medicaments and other excipients. The patent quoted, “Core materials may include hydrophobic components, such as flavor oils or vegetable oils, as well as hydrophilic components”. Anyone knowledgeable in the preparation of making capsules will agree that oils are not preferred in the “capsule shell-forming composition”. The patent further quoted, “The core compositions, as previously mentioned, may take a variety of physical forms, such as powders, granules, gels, pastes or liquids”. It was clear that the inventors intended to fill their rapidly dissolving gelatin capsules with the “core materials” prepared using the core composition, which included active medicaments. The inventors did not intend to add the “actives” in the “capsule shell-forming composition”. Also, the inventors did not teach to make capsules using polymeric materials such as HPMC (hydroxypropyl methylcellulose).
There are mainly two methods to prepare capsules: pin dip-coating and heat-melting. A liquid mass is produced by dissolving the capsule shell-forming compositions in a solvent system or by melting at an appropriate temperature. In the dip-method, plurality of pins maintained at a certain temperature is dipped in the solution and is withdrawn at a pre-determined rate while spinning. The pins coated with capsule composition are then dried at a gradual rate. The capsules (body and cap) are separated from the pins and are trimmed to an exact length. The method has been employed to prepare the body and cap of the capsules. The body and cap are joined or fitted together or cooperatively engaged and a logo is printed, if necessary.
InnerCap (http://www.innercap.com/) proposed combination capsules in which a capsule may contain another small capsule or a tablet along with granules (multiphase, multi-compartment capsule technology). The granules may be made up of beads or other forms, which may contain more than one type of drugs. This way, more than one type of drug may be combined in the same capsule. This is a different technology compared to the current disclosure.
Soft gelatin capsules are another form of capsules in which a liquid core material is filled. It has created a niche market of its own in the drug delivery technology. In coming times, soft non-gelatin may be introduced in the market due to advent of new polymeric systems.